PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF), a life-shortening genetic disease is characterized by abnormalities in the pulmonary, digestive, and other secretory systems leading to increased airway and systemic inflammation, oxidative stress, nutrient malabsorption, tissue catabolism, and ultimately, respiratory failure and premature death. Adequate nutritional status in CF, including maintenance of skeletal muscle (fat-free) mass, is tightly correlated with lung function and survival in this population. However, relatively little research exists to guide evidence- based optimal dietary recommendations regarding specific nutrients and food patterns in CF. Recent advances in high-resolution metabolomics (HRM) provide a unique opportunity to broadly explore metabolism and underlying pathways relevant to nutrition, disease exacerbation, and treatment in CF. Preliminary HRM data from Dr. Alvarez's K01-supported research (K01 DK102851) indicated an enhanced catabolic state in adults with CF, as evidenced by dysregulation of plasma amino acids and lipids and their metabolic intermediates. The data also suggested that high-dose vitamin D3--previously shown to improve clinical outcomes--may mitigate catabolism in these subjects during an acute pulmonary exacerbation. Furthermore, key clinical outcomes before vitamin D3 intervention, such as lung function, were correlated with metabolic pathways directly linked to dietary intake and nutritional status. The purpose of this R03 study is to use plasma HRM with advanced bioinformatics to: 1) identify specific nutrient-related metabolic processes that differ as a function of clinical status and are linked to important clinical outcomes; and 2) confirm an anti-catabolic/pro-anabolic effect of high-dose vitamin D3 in a completed prospective, randomized controlled trial. The overall goal of this project is to obtain new insight into the CF catabolic state during acute illness and recovery that will inform the design of future nutritional interventions to prevent depletion of fat-free mass. Specific aims are to use plasma HRM to: 1) compare the catabolic state of adults with CF during clinical stability vs. during acute pulmonary exacerbation, using healthy adults and adults with non-CF bronchiectasis as controls; 2) investigate whether high-dose vitamin D3 has long-term anti-catabolic/pro-anabolic effects in adults with CF initially hospitalized for an acute pulmonary exacerbation; and 3) conduct metabolome-wide association studies in Aim 1 and 2 CF subjects to determine if nutrient-related pathways are linked to convalescence and clinical outcomes over time. This R03 grant, in combination with Dr. Alvarez's K01 training, will accelerate her transition to independence and will provide strong preliminary data for subsequent R01 studies. These will focus on the pathophysiology of catabolism in CF and development of new nutritional strategies to improve the health and quality of life in adults with CF, consistent with the mission of the NIDDK.